EP0256532B1 - Use of dihydrobenzopyrane derivatives - Google Patents

Description

   worin R Wasserstoff oder niederes Alkyl bedeutet,
eines Enantiomeren davon oder, falls R Wasserstoff bedeutet, eines pharmazeutisch annehmbaren Salzes davon mit einer Base zur Herstellung von pharmazeutischen Präparaten gegen Enteritis und anderen durch Leukotrien vermittelten Entzündungen der intestinalen Mucosa.The present invention relates to the use of a compound of the general formula

where R is hydrogen or lower alkyl,
an enantiomer thereof or, if R is hydrogen, a pharmaceutically acceptable salt thereof with a base for the manufacture of pharmaceutical preparations against enteritis and other inflammations of the intestinal mucosa mediated by leukotriene.

The compounds of the formula I can be administered in various ways, preferably orally, but also rectally or parenterally. The pharmaceutical preparations which contain one of the above compounds as the active ingredient are in the form of oral dosage forms for the purpose of releasing the active ingredient in the small and large intestine, or as rectal or parenteral dosage forms.

The above compounds and preparations can be used to effectively treat intestinal mucosal inflammation including enteritis which, it appears, is mediated by leukotriene.

The term "enteritis" is often used to refer to inflammation of the intestine or other parts of the intestinal tract, which as a common feature have chronic or acute inflammation of the gastrointestinal mucous membranes. Various forms generally include Crohn's disease of the ileum and colon, ulcerative colitis, neonatal necrotizing enterocolitis, and food allergies. Histopathologically, they are characterized by ulceration, pseudomembrane, radiologically visible lesions, edema and the formation of inflammatory cells and, as symptoms, result in diarrhea, abdominal pain, weight loss and hypoproteinemia. Descriptions can be found in the following references: Northfield, Drugs 14 : 198-206 (1977); Blaker et al., Eur. J. Pediatr. 139 : 162-164 (1982); Singleton, The Gastroenterology Annual, pp. 268-310 (1983); Saco et al., J. Amer. Acad. Dermatol. 4 : 619-629 (1981); Prantera et al., Ital. J. Gastroenterol. 13 : 24-27 (1981); Sales et al., Arch. Int. Med. 143 : 294-299 (1983), and Ament, Inflammatory Bowel Diseases, Martinus Nijhoff Publ., Boston, Mass., Pp. 254-268 (1982). Inflammation of the mucous membranes of other parts of the body is less common gastrointestinal tract, such as duodenitis, jejunitis and proctitis.

Among the active ingredients which are useful for the treatment of such diseases are sulfasalazine and other compounds which release 5-aminosalicylate in the intestine, corticosteroids, metronidazole and cholestyramine, cf. Sack and Peppercorn in Pharmacotherapy 3 , 158-176 (1983).

The compounds of formula I, their enantiomers and their pharmaceutically acceptable salts have previously been described for other purposes in European Patent Publication No. 129 906, in particular their use as antiallergics including their use for the treatment of asthma. Other dihydrobenzopyran derivatives have been described in European patent publications 139809 (May 8, 1985) and 150447 (June 7, 1985) as leukotriene inhibitors which are useful for the treatment of allergies and inflammatory diseases such as rheumatoid arthritis. European Patent Publication No. 156 233 describes the use of structurally different benzopyran derivatives (leukotriene antagonists) for the production of cytoprotective pharmaceutical preparations for the treatment of erosive gastritis, esophagitis and inflammatory bowel diseases. The present invention is based on the knowledge that the compounds specifically described here are very particularly useful and extraordinarily potent in combating the above-mentioned inflammation of the mucous membrane.

The term "leukotriene-mediated" is used to indicate that the substance leukotriene actively participates in causing inflammatory skin disease or in manifesting the symptoms associated therewith, or both.

In the context of the present invention, the term “lower alkyl” denotes straight-chain or branched saturated hydrocarbon radicals with 1-7 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, hexyl and heptyl.

The terms "HAL" and "halogen" used in the present specification refer to the four halogens bromine, chlorine, fluorine and iodine, preferably bromine, chlorine and iodine.

worin Rʹ niederes Alkyl bedeutet, und HAL die obige Bedeutung besitzt.The compounds of the formula I can be prepared as described below in accordance with reaction scheme I:

wherein Rʹ is lower alkyl, and HAL has the above meaning.

The reaction of the compound of formula II (a known compound) with a compound of formula III according to reaction scheme I to a compound of formula Ia is carried out under anhydrous conditions in an inert solvent, for example in acetone, acetonitrile, Methyl ethyl ketone, diethyl ketone, dimethylformamide or the like. The reaction is carried out at the reflux temperature of the reaction mixture, preferably at a temperature in the range from about 70 ° C to about 100 ° C, and in the presence of an acid-binding agent such as potassium carbonate or the like. A mixture of acetone and dimethylformamide is preferably used as the solvent. The compound of formula Ia obtained can be isolated by means of conventional methods, for example by crystallization, chromatographic methods or the like.

If desired, the compound of the formula Ia, which itself can be used according to the invention, can be converted into a compound of the formula Ib by hydrolysis. The hydrolysis is carried out with an alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide or the like, in a mixture of water and a water-miscible solvent, e.g. methanol, ethanol, tetrahydrofuran or the like, at a temperature in the range of about room temperature (e.g. 20 ° to 25 ° C) to the reflux temperature. The compound of formula Ib obtained can be isolated by means of conventional methods, for example by extraction, crystallization, chromatographic methods or the like.

The use according to the invention can also be carried out with pharmaceutically acceptable salts of compounds of the formula I in which R is hydrogen. These salts can be prepared by reacting an acid of formula I or an enantiomer thereof with a base which has a non-toxic and pharmacologically and pharmaceutically acceptable cation. In general, the present invention encompasses salts with all bases which form a salt with the present carboxylic acids and whose pharmacological properties are not disadvantageous physiological Cause reactions when ingested by a warm-blooded animal. Suitable bases are, for example, alkali metal and alkaline earth metal hydroxides and carbonates, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate and the like, ammonia, primary, secondary and tertiary amines, such as monoalkylamines, dialkylamines, trialkylamines, nitrogen-containing heterocyclic amines, for example piperidine, such as basic amino acids Lysine, and the like. The pharmaceutically acceptable salts thus obtained are functional equivalents of the corresponding 3,4-dihydro-2H-1-benzopyranecarboxylic acid of the formula Ib and its enantiomers. The person skilled in the art has no difficulty in recognizing the scope of the salts which can be used therapeutically, since the variety of the salts which can be used according to the invention is limited only by the criteria that the bases used for the preparation of these salts are non-toxic and physiologically acceptable.

   worin HAL und Rʹ obige Bedeutung besitzen.The starting materials of formula III used for the preparation of compounds of formula I are known or, as described below, can be prepared according to reaction scheme II:

wherein HAL and Rʹ have the above meaning.

The reaction of a compound of formula IV with a compound of formula V according to reaction scheme II to a compound of formula III is carried out in an inert organic solvent such as dimethylformamide, acetone, methyl ethyl ketone, acetonitrile or the like, preferably in acetonitrile. The reaction is carried out in the presence of a base, for example an alkali metal carbonate such as potassium carbonate, sodium carbonate or the like, or an alkali metal hydride such as sodium hydride or the like, at a temperature in the range from about 20 ° to about 150 ° C, preferably at room temperature (e.g. 20 ° up to 25 ° C). The compound of formula III obtained can be isolated by means of conventional methods, for example by means of crystallization, extraction, chromatography or the like.

The compounds of formula V used as starting materials are known or can be known per se Methods are made.

   worin Rʹ obige Bedeutung besitzt.The starting materials of the formula V used for the preparation of compounds of the formula III are known or, as described below, can be prepared in accordance with reaction scheme III:

where Rʹ has the above meaning.

According to reaction scheme III, a compound of formula VI, which is known or can be prepared by methods known per se, is hydrogenated to a compound of formula Va. In particular, the reaction is carried out in the presence of a catalyst, for example palladium on carbon, in a solvent such as the lower fatty acids, preferably in acetic acid, at a temperature in the range from about 20 ° C to about 100 ° C, preferably at 25 ° C and at elevated pressure, preferably at 50 psi (344.75 kPa). The compound of formula Va obtained can be isolated by conventional methods.

The compound of formula Va is then by means of a suitable acetylating agent, for example by means of an acetic acid halide or anhydride, preferably acetic anhydride, in a suitable base, for example in a lower alkylamine or the like, preferably in pyridine, at a temperature in the range of about 0 ° C. up to about 150 ° C, preferably at 25 ° C, converted into the corresponding acetyl derivative of formula V. The compound of formula V obtained can be isolated by conventional methods.

The compounds of formula I have an asymmetrically substituted carbon atom and are therefore normally obtained as racemic mixtures. Such racemates can be cleaved into the optically active isomers by methods known per se. Certain racemic mixtures can be precipitated as eutectics and then separated. However, the splitting is preferably accomplished chemically. In this case, the corresponding diastereoisomers are prepared from the racemic mixture of compounds of the formula I in which R is hydrogen using an optically active cleaving agent. Suitable cleavage agents are, for example, optically active bases, such as d - (+) - or 1 - (-) - α-methylbenzylamine. The diastereomeric salts obtained are separated by fractional crystallization and then converted into the corresponding optical isomers. The present invention thus comprises the use of racemates of compounds of the formula I and their optically active isomers (enantiomers).

Further details and more specific methods for the preparation of compounds of the formula I can be found in the above-mentioned European Patent Publication No. 129 906.

Because of the nature of the disease to be treated, the compounds of formula I are preferably administered orally, which results in the surface of the inflamed intestinal tissues being directly exposed to the action of the compound administered. For oral use, these compounds can be administered in the form of tablets, pills, capsules, powders, granules or microcapsules. Suitable inert pharmaceutically acceptable carriers for such pharmaceutical forms are, for example, talc, starch, lactose and the like. However, they can also be administered in the form of aqueous solutions, suspensions, elixirs or alcoholic solutions. For example, they can also contain flavorings, colorants, thickeners or other conventional pharmaceutical auxiliaries. In a typical embodiment, the compounds of the formula I are formulated into preparations which slow down the active ingredient and release in particular in the lower parts of the intestine.

On the other hand, the compounds of the formula I can also be administered parenterally or rectally by means of appropriate dosage forms which contain suitable carrier materials. Production methods known per se and familiar to any person skilled in the art can be used for their production.

In the sense of a more detailed description, the experimental part of the present description also contains examples of dosage forms which can be administered orally, rectally and parenterally according to the invention.

The dosage of compounds of formula I and the frequency of administration depend on the severity of the inflammation, on the age of the patient to be treated, as well as on the potency, the duration of action and the concentration of the specific compound which is used as the active ingredient.

In the context of the use of the compounds of the formula I according to the invention, dosages in the range from about 50 to 4000 mg / day, preferably from about 150 to about 500 mg / day, can be expected, these being able to be administered as a single dose or in multiple doses per day.

The valuable anti-inflammatory properties according to the invention can be determined using standard pharmacological methods in warm-blooded animals. The methods described below are examples of such standard methods:

A: Experiment with the rat colon mucosa, in vitro:

The bioassay system of the experiment with the mucosa of the rat colon is based on the measurement of the changes in the salt transport through the animal tissue caused by absorption or secretion, whereby the changes by Ussing et al. uses the standard short-circuit technique described, Acta Physiol. Scand. 23 : 110-127 (1951). Diarrhea is the most common symptom of gastrointestinal inflammation and occurs in all types of enteritis. Pantera, et al., Ital. J. Gastroenterol. 13 : 24-27 (1981); Sales, et al., Arch. Int. Med. 143 : 294-299 (1983); Hodgson, Br. J. Clin. Pharmac. 14 : 159-270 (1982). Diarrhea is caused by a decrease in salt absorption or an increase in salt secretion in the intestine and can be achieved by the above-mentioned method by Ussing et al. be quantified in vitro. A 1 cm segment of the colon is removed from animals weighing 200-250 g, this is treated in vitro with leukotrienes or bradykinin, which promote salt secretion, and the change obtained in net salt transport, which is present in the presence and in the absence of 6- Acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid is obtained as an inhibitor. Tissue samples are attached in pairs in Ussing chambers and with automatic tension clamps (from the University of Iowa Bioengineering Department) shorted. The preparations are then allowed to balance for 15 minutes. The tissue samples arranged in pairs are treated on the one hand with bradykinin (or leukotrienes) and on the other hand with bradykinin (or leukotrienes) and a certain concentration of the inhibitor. The answers received are then compared and the inhibition calculated as a percentage.

Bradykinin is used in this experiment because it is known that this substance stimulates the phospholipase A₂, which leads to the production of leukotrienes, which are known to promote salt secretion in intestinal tissue samples in vitro. Musch, et al., J. Clin. Invest. 71 : 1073-1083 (1983); Hojvat, et al., J. Pharmacol. Exp. Ther., 226 : 749-755 (1983); Cuthbert, et al., Br. J. Pharmac. 82 : 597-607 (1984): Musch, et al., Science 217 : 1255-1256 (1982). The activity of bradykinin in the production of leukotrienes is suppressed by inhibitors of leukotriene biosynthesis; Cuthbert, et al., Br. J. Pharmac. 75 : 587-589 (1982); Musch, et al., J. Clin. Invest., Supra; Hojvat, et al., J. Pharmacol. Exp. Ther., Supra.

The results obtained are shown in Table 1 and in FIG. 1. These show the ability of the racemic 6-aceyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,3-dihydro-2H-1-benzopyran-2-carboxylic acid, the secretory activity to reduce leukotrienes (Table 1) and bradykinin (Figure 1) according to the invention. Table 1 Effect of the inhibitor on leukotriene-induced electrolyte secretion by the colon of the rat (in vitro) Inhibitor concentration in micromoles (mM) % Inhibition against leukotrienes * LTB₄ LTC₄ LTD₄ LTE₄ 1 44.4 ± 13.1 9.5 ± 19.2 30.8 ± 15.4 29.8 ± 15.0 10th 69.6 ± 11.9 57.1 + 19.7 62.4 ± 10.0 44.2 ± 9.8 LT = leukotriene * All inhibition values given in percent are based on measurements on 6 test animals.

B. Antibiotic-induced colitis in hamsters, in vivo

Male, 80-120 g Syrian hamsters (LUG) are given a single dose of 175 mg / kg clindamycin phosphate or clindamycin hydrochloride intraperitoneally to induce colitis. About 7 hours after this injection, the animals are administered the compound to be tested orally or intraperitoneally. This therapy is repeated twice a day for a further 4 days. For oral administration, the compound to be tested was suspended in water or dissolved in dimethyl sulfoxide and administered using a gastric tube. The effect of the therapy was determined by the so-called "hazard" ratio. This is the ratio of the mortality rate of animals that have been treated with the compound to be tested compared to the animals that have been treated with vehicle only. The mortality rate was determined twice a day and was evaluated by comparing the survival curves for each group. For each group of experimental animals, the Kaplan-Meier estimate of the survival curve was calculated and the Mantel-Cox test was used to calculate the survival curve compare the inhibitor-treated group with that of the vehicle-treated group only. A hazard ratio of 1.0 means that the effect of the therapy is no better than that achieved with the vehicle alone, while a hazard ratio (> 1.0) means that the therapy has a survival rate compared to that group which has only been treated with the vehicle.

The racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid was found at oral doses was active in the range of 10 to 100 mg / kg. Two known leukotriene inhibitors, namely 7 - [- 3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropoxy] -4-oxo-8-propyl-4H-1-benzopyran-2- carboxylic acid (see compound 1) and 7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -4-oxo -8-propyl-4H-1-benzopryran-2-propane carboxylic acid (see compound 2), were found to be inactive at oral doses of 10 mg / kg (see Table 2).

Apart from the fact that the racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid has the survival rate of those with In animals treated with clidamycin, this compound also reduced diarrhea and significantly improved the histopathology of the cecum and colon. It is particularly noteworthy that the cecum of the hamsters treated with clindamycin was initially characterized by edema, extensive bleeding and congestion, necrosis and focal erosions of the mucous membranes, and by an increased infiltration of the mucous membranes by inflammatory cells. Similar, but less severe effects were seen with the colon. In most cases, the effects were reduced or completely eliminated by the administration of 60 or 100 mg / kg of the above compound.

The racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopryran-2-carboxylic acid was together with its methyl and hexyl esters in the experiment with clindamycin-induced colitis in hamsters evaluated in vivo side by side, as described above. The test substances were administered orally in doses of 20 micromoles / kg body weight. The results obtained with the esters are summarized in Table 3 below. The comparison with the corresponding carboxylic acid, for which a hazard ratio of 2.87 has been determined (see Table 2), is favorable Table 3 Therapeutic activity of leukotriene inhibitors against antibiotic-induced colitis (in vivo) Test substance Dose (20 µmol / kg) Hazard ratio n Racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-2-benzopyran-2-carboxylic acid methyl ester 20th 3.42 30th Racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid methyl ester 20th 1.64 30th racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 20th 1.45 30th n = number of test animals

C. Acetic Acid-Induced Colitis in Rats, In Vivo

The acetic acid-induced colitis bioassay in rats has been described by JE Krawisz et al. in Amer. J. Proc. Gastro. Col. Rec. Surg. 31 , 11-18 (1980) and P. Sharon and WF Stenson in Gastroenterology 88 , 55-63 (1985) and 86 , 453-460 (1984). Acetic acid-induced colitis is characterized by a migration of inflammatory cells into the colon. The number of such cells in the mucosa can be determined by measuring the activity of myeloperoxidase, a marker enzyme for these cells. A positive desired effect is shown by a reduction in the high myeloperoxidase level, which is caused by the acetic acid. Male rats weighing 150-300 g (Sprague-Dawley) are orally pretreated for 2 days, twice daily, either with the vehicle (water or dimethyl sulfoxide) or with the test substance suspended in water or dissolved in dimethyl sulfoxide. Treated on day 3 the animals are injected again as on the two previous days, anesthetized with Metofan, 2 ml 2.5%. Acetic acid by means of a syringe into the lumen of the colon and immediately afterwards 3 ml of air and a rinsing solution, consisting of 3 ml of phosphate-buffered saline, remain in the lumen long enough to induce inflammation, but without causing severe necrosis or irreversible damage ). About 16 hours later, the animals are given another dose of the test substance in the same amount. The animals are sacrificed 24 hours after the treatment with the acetic acid, whereupon the colon mucosa is surgically removed and homogenized in an aqueous buffer at pH using a suitable mixer. The activity of the myeloperoxidase in the homogenate is determined using o-phenylenediamine as the chromogen, as by A. Voller, DE Bidwell and A. Bartlett in The Enzyme Linked Immunosorbent Assay (ELISA), Zoological Soc., London, 1979, pages 29-30 described, measured. Control animals are pretreated with the vehicle and then treated with saline instead of acetic acid.

Using the test described above, the racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid was also reacted with Phenidon compared, a known inhibitor of leukotriene synthesis. The results shown in FIGS. 2 and 3 were obtained. As can be seen, phenidone was active at oral doses of 100 and 200 mg / kg (Figure 2), while the racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] - 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid was active even at the smaller oral doses of 30 and 90 mg / kg (Figure 3).

D. Carrageenin-induced colitis in guinea pigs, in vivo

The carrageenin-induced colitis bioassay in guinea pigs is by AB Onderdonk in Inflammatory Bowel Diseases, Martinus Nijhoff Publ., Boston, Massachusetts, pages 126-134 (1982) and in Human Intestinal Microflora in Health and Disease (DJ Hentger. ed), Academic Press, New York, 1983, pages 447-479. The red algae-derived polysaccharide jotacarrageenin causes colitis in guinea pigs, which is similar to ulcerative colitis in humans. Male and female, 400-650 g guinea pigs (Hartley) received a 3 percent daily from drinking water. Degraded carrageenin solution. After about 7 days, the experimental animals began to develop diarrhea, lost weight and became lethargic. After the test animals were given carrageenin for 14 days, the diarrhea was quantified by measuring water transport into the distal part of the colon by simple pass perfusion using 14C-polyethylene glycol 4000 (PEG 4000) as a marker. Control animals received an aqueous drinking solution containing 3 percent. mannitol instead of carrageenin. At the same time, randomly selected experimental animals from these two groups were treated orally with the test substance twice a day.

The racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid was tested in this test with the sulfasalazine, a standard inhibitor in this test system. The results are shown in FIGS. 4 and 5.

As can be seen, at an oral dose of 100 mg / kg, the sulfasalazine restores the water transport in the colon of the sick test animals from a secretory level to a level which roughly corresponds to that of the control test animals (FIG. 4). On the other hand, test animals which were treated with racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid showed at lower dosages of 10 and 30 mg / kg, respectively, water transport rates which were practically the same as those of the control test animals (FIG. 5).

example 1

Oral formulation (tablet) Components mg / tablet Racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 250.0 mg Lactose 50.0 mg Strength 25.0 mg Polyvinyl pyrrolidone 2.5 mg Magnesium stearate 2.5 mg total weight 330.0 mg

Procedure :

A mixture of the pulverized constituents is granulated with the polyvinylpyrrolidone in solution and pressed into tablets. The tablets are then coated by spraying them with the solution described below or rotating them in a bath containing this solution: % By weight Hydroxypropyl methyl cellulose phthalate 6 Alcohol 3A 47 Methylene chloride 47 total weight 100%

The coated tablets obtained are resistant to gastric juice, but dissolve in the intestinal juice if they are examined in an in vitro dissolution test according to the USP.

Example 2

Oral formulation (soft gelatin capsule) Components mg / capsule Sodium salt of racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 261.0 * mg Triglycerides (medium chain length) 229.0 mg Sodium silicate 10.0 mg total weight 500.00 mg * corresponds to 250 mg of free acid

Procedure :

The ingredients are prepared in the form of a suspension, which is then filled into soft gelatin capsules. The capsules are then coated with a suitable coating agent so that they are resistant to gastric juice but dissolve in the intestinal juice if they are examined in an in vitro dissolution test according to the USP.

Example 3

Oral formulation (microcapsules) Components mg / dose racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 250 mg Polyvinyl pyrrolidone 25 mg Strength 50 mg Total weight / dose 325 mg

Procedure :

The microcapsules are produced by wet granulation and then coated with the polymeric solution of the following composition by spraying the surface of the microcapsule in a rotating, suitable container. % By weight Polymethacrylic acid polymer 5.0 Ethyl cellulose 1.0 acetone 10.0 Isopropyl alcohol 84.0 total weight 100.0%

The coated microcapsules are resistant to the intestinal juice, but dissolve in the intestinal juice when examined in an in vitro dissolution test according to the USP.

Example 4

Oral formulation (tablet) Components mg / tablet 100 mg 600 mg racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 100 mg 600 mg Lactose 30 mg 100 mg Pre-gelatinized starch 4 mg 25 mg Microcrystalline cellulose 20 mg 120 mg Modified starch 5 mg 25 mg Magnesium stearate 1 mg 8 mg total weight 160 mg 878 mg

Procedure :

The racemic 6-acetyl-7- [5 (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2 - carboxylic acid, the lactose, the pregelatinized starch and the microcrystalline cellulose are mixed and granulated in the water. The granulated material is dried at 45-50 ° C and ground. The modified starch and magnesium stearate are then added and the resulting mixture is compressed into tablets.

Example 5

Oral formulation (tablet) Components mg / tablet 100 mg 600 mg racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 100 mg 600 mg Lactose 40 mg 200 mg Polyvinyl pyrrolidone 4 mg 24 mg modified starch 4 mg 24 mg Magnesium stearate 1 mg 6 mg total weight 149 mg 856 mg

Method:

The racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid, the lactose and the modified starch, granulated with polyvinylpyrrolidone in water or alcohol, dries the granulated material at 45-50 ° C, ground, adds the magnesium stearate and compresses the resulting mixture into tablets.

Example 6

Oral formulation (capsules) Components mg / capsule 100 mg 600 mg racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 100 mg 600 mg Lactose * 50 mg - pre-gelatinized starch ** 5 mg 30 mg Talk 4 mg 24 mg Magnesium stearate 1 mg 6 mg total weight 160 mg 660 mg * can be replaced by dicalcium phosphate dihydrate, mannitol or sorbitol ** Can be replaced by hydroxypropyl methyl cellulose, gelatin or silicates

Procedure :

The racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid, the lactose and the pre-gelatinized are mixed Starch, granulated in water, dries the granulated material at 45-50 ° C, ground, adds the talc and the magnesium stearate and fills the resulting mixture in soft gelatin capsules.

Example 7

Parenteral formulation Components mg / ml racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 10 mg Mannitol * 20 mg Sodium hydroxide and / or hydrochloric acid to adjust the pH q.s. Water (for injection), s.q. ad 1.0 ml Total volume 1.0 ml * can be replaced by lactose

Procedure :

The racemic 6-acetyl-7- [5 (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and the mannitol are dissolved in water and adjusted the pH. The solution is then lyophilized in a suitable container (removal of the water).

Example 8

Parenteral formulation Components Percent by weight racemic 6-acetyl-7- [5- (4-acetyl-3-hydoxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 1.0% Benzyl alcohol * 1.0% Propylene glycol ** 10.0% Emulphor ** 5.0% Phosphate buffer, s.q. pH 7.5 Water (for injection), s.q. ad 100% * can be replaced by thimerosal, phenol, methyl and propylparaben, benzothonium chloride or chlorobutanol ** Can be replaced by polyethylene glycol, alcohol, dimethylacetamide, glycerin, povidone, lecithin, sorbitan monooleate and trioleate

Procedure :

The phosphate buffer is dissolved in part of the water, the benzyl alcohol, the propylene glycol and emulphor are added to the buffered solution while stirring, then the racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2- propyl-phenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid in the solution, adjusts the pH, adds water to the desired amount and fills the solution obtained in a suitable container.

Example 9

Rectal formulation (suppositories) Components mg / suppository 100mg 1000mg racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 100 mg 1000 mg Suppository mass *, s.q. ad 1000 mg 2000 mg total weight 1000 mg 2000 mg * contains semi-synthetic glycerides, mixtures of triglycerides, such as Witepsol H15 from Dynamit Nobel Chemicals, and the polyethylene glycols 400 and 4000, individually or in combination if required

Procedure :

The racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid is dispersed in the molten suppository mass and fills the resulting mass into suitable suppository forms.

Example 10

Rectal formulation (suppositories) Components mg / suppository 100 mg 1000 mg racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 100 mg 1000 mg Sorbitan trioleate 100 mg 600 mg Cocoa butter, s.q. ad 1000 mg 2000 mg total weight 1000 mg 2000 mg

Procedure :

The cocoa butter is melted, and the sodium salt of the racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2 is dispersed -carboxylic acid and the sorbitan trioleate in it and fill the mass into suitable suppository forms.

Example 11

Rectal wording (enema) Components mg / dose 100 mg 1000 mg Sodium salt of racemic 6-acetyl-7- [5 (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 100 mg 1000 mg Polyethylene glycol 400 10 ml 15 ml Water for injection, s.q. ad 120 ml 180 ml Total volume / dose 120 ml 180 ml

Procedure :

The sodium salt of racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and the polyethylene glycol 400 are premixed and then dissolved in water for injections. This solution is then filled into suitable containers from which it can then be dispensed by pressing.

Example 12

Analogously to Examples 1-11, tablets, capsules, microcapsules, parenteral and rectal formulations can be prepared which contain the following compounds:
Racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid methyl ester and
Racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid hexyl esters.

Examples 13-15 below describe the preparation of the still new methyl and hexyl esters of the racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H -1-benzopyran-2-carboxylic acid.

Example 13 Preparation of the racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid methyl ester

A mixture of 2 g racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid, 97 mg p -Toluenesulfonic acid monohydrate and 25 ml of methanol is heated to reflux with stirring for 19 hours. The solution obtained is cooled and evaporated in vacuo to give a solid residue which is taken up in ethyl acetate. The ethyl acetate solution is washed with saturated aqueous sodium bicarbonate solution, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is chromatographed on 100 g of silica gel. After elution with a 1: 1 mixture of hexane and ethyl acetate, 2.06 g of the pure methyl ester are obtained. By recrystallization from acetonitrile, the racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid methyl ester is obtained as a colorless, amorphous solid. Analysis calculated for C₂₉H₃₆O₈: C, 67.96%; H, 7.08%. Found: C, 67.69%; H, 6.98%.

Example 14 Preparation of the racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid methyl ester

A mixture of 20.2 g racemic 6-acetyl-7- [5- (bromopentyloxy] -3,4-dihydro-2H-1-benzopyran -2-carboxylic acid methyl ester, 11.0 g 2,4-dihydroxy-3-propylacetophenone , 25.4 g of anhydrous potassium carbonate, 436 ml of dry acetone and 218 ml of dry N, N-dimethylformamide are heated to boiling under stirring and under reflux for 5.5 hours, the reaction mixture is cooled and diluted with ethyl acetate Washed water and saturated sodium chloride solution, then dried over magnesium sulfate, filtered and evaporated in vacuo to give 28.3 g of an amber oil. This material is dissolved in a 1: 1 mixture of hexane and ethyl acetate and by means of preparative HPLC (Waters 500 A , 2 columns) cleaned using hexane / ethyl acetate (1: 1) as eluent. This gives 24.83 g (96.8%) of the desired ester as an oil which crystallizes on standing to a colorless solid.

Example 15 Preparation of the racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid hexyl ester

In a 1-1 flask equipped with a mechanical stirrer, a Dean-Stark apparatus, a reflux condenser and a calcium chloride tube, 50.0 g of racemic 6-acetyl-7- [5- (4-acetyl-3- hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid, 10.3 g of 1-hexanol, 1.0 g of p-toluenesulfonic acid monohydrate and 500 ml of toluene. The mixture is then heated to boiling under an inert gas atmosphere for 2 hours, the water of reaction formed being continuously removed. After cooling to room temperature, the brown solution obtained is washed successively twice with 100 ml of saturated saline, twice with 100 saturated aqueous sodium bicarbonate solution and twice with 100 ml of saturated saline. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure first at 4.55 kPa and finally in a high vacuum at 13 Pa and at 45 ° C., giving a brown oil. This oil is treated with 370 ml of alcohol at room temperature until crystallization begins, after which the mixture is placed in the refrigerator at 12 ° C. overnight. The crystals are then filtered off and air dried overnight. 50.4 g (86%) of racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopryran-2- carboxylic acid hexyl ester as a whitish solid with a melting point of 70-72 ° C.

Claims (2)

1. The use of a compound of the general formula

   

      wherein R signifies hydrogen or C₁-C₇ alkyl,
   of an enantiomer thereof or, where R signifies hydrogen, of a pharmaceutically acceptable salt thereof with a base for the manufacture of pharmaceutical preparations against enteritis and other leukotriene-mediated inflammations of the intestinal mucosa.
2. The use of racemic 6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid in accordance with claim 1.

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